Receptor Implicated in Diabetics' Increased Risk of Heart Disease

DURHAM, N.C. - Duke University Medical Center researchers believe that increased levels of a receptor and an inhibitory protein in the heart may explain why heart disease patients with diabetes are at a much greater risk of cardiovascular disease or heart attacks than patients without diabetes.

The researchers found that while levels of the protein, called Gαi, gradually increase with age, this increase is almost twice as high in diabetic patients. This finding is important, the researchers said, because elevated levels of this receptor protein can lead to dilated cardiomyopathy, in which the heart loses its ability to pump blood effectively throughout the body. Untreated, this condition often leads to congestive heart failure.

Heart disease is a major complication of diabetes, with about 70 percent of deaths in patients with diabetes due to cardiac complications, researchers said.

"We see an increase in the levels of Gαi-coupled receptor in the heart as we age, but the increase is not significant," said Duke pharmacologist Madan Kwatra, Ph.D., principal investigator of a study whose results were published Aug. 26, 2004, in the journal Diabetes. "However, when the effects of aging are combined with the presence of diabetes, the increase becomes significant. In addition, the study also found an increase in Gαi in atrium from diabetic subjects.

"The results of our studies suggest a molecular explanation for the increased risk of cardiac disease in patients with diabetes, since increased activity of Gαi has been shown to lead to the development of dilated cardiomyopathy," Kwatra said. "This is the first demonstration of a diabetes-induced increase in Gαi in the human heart."

Gαi mediates signaling through a family of G protein-coupled receptors (GPCR), which are molecules on the cell surface that respond to external hormones to affect cardiac function. For example, beta-adrenergic receptors (βAR) - which respond to the hormones epinephrine and norepinephrine in the so-called "fight-or-flight" response to increase cardiac output - are also members of this family. Gαi is one of a number of similar proteins that can prevent these hormones from "coupling" to βARs, thereby decreasing the heart's ability to contract.

Kwatra's team, which for years has been studying the effects of age on GPCR signaling in the heart, collected samples of human atria, the upper chambers of the heart, from 51 patients between the ages of 41 and 85, 95 percent of whom had Type II diabetes. The patients had undergone surgery that required the use of the heart-lung machine. In order to hook up the circulatory system to the heart-lung machine, a small "plug" of atrial tissue must be removed to attach the tubing.

For their experiments, the researchers focused on cardiac muscarinic acetylcholine receptor (mAChR), which works through Gαi to help regulate the autonomic functioning of the heart. They measured the "density," or amount of these receptors, in the atrial tissue of the patients with diabetes and compared these findings to the levels of age-matched patients without diabetes.

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"We found that the cardiac mAChR density does increase with age, but that the increase is statistically significant only in the patients with diabetes," Kwatra explained. "These findings are consistent with previous studies which have shown that the induction of diabetes in animals enhanced the effects of mAChR on heart function."

Kwatra added that evidence from other studies also shows that an increase mAChR density in heart muscle cells can lead to arrhythmias, especially atrial fibrillation, which can be life-threatening. People with diabetes are known to have an increased incidence of atrial fibrillation, he said.

Based on his research on human tissue and animal models, Kwatra believes that changes in Gαi should be considered when studying the underlying biochemical causes of heart disease.

Kwatra plans further research to determine whether or not Gαi levels taken from blood samples can be correlated with levels in the atria, as well as studies of the ventricles, the other two pumping chambers of the heart. In collaboration with Duke endocrinologist Mark Feinglos, M.D., the team will soon begin a study to measure levels of Gαi in the blood cells of the patients with Type II diabetes.

"Beta-blockers, which have been quite effective in improving the heart function of patients with congestive heart failure, would seem to be a likely candidate to reduce the risk of heart disease in people with diabetes because these drugs have been shown to decrease cardiac Gαi levels," Kwatra said. "That class of drugs is already very well understood and has very few side effects."

By blocking the stimulatory effects of epinephrine and norepinephrine, beta-blockers reduce heart rate and blood pressure. The drugs have been used for 20 years for different ailments, but are primarily used to help treat high blood pressure, chest pain, and heartbeat irregularities.

Kwatra's research was supported by the National Institute of Aging, part of the National Institutes of Health. Other Duke team members were Mark Richardson, Ph.D., and Jason Kilts, Ph.D.

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